miR-17-5p attenuates kidney ischemia-reperfusion injury by inhibiting the PTEN and BIM pathways

Ming Ma; Lei Fu; Zihao Jia; Qiang Zhong; Zhongli Huang; Xianding Wang; Yu Fan; Tao Lin; Turun Song

doi:10.21037/atm-21-4678

miR-17-5p attenuates kidney ischemia-reperfusion injury by inhibiting the PTEN and BIM pathways

Ann Transl Med. 2021 Oct;9(20):1545. doi: 10.21037/atm-21-4678.

Authors

Ming Ma^#^{1

2}, Lei Fu^#³, Zihao Jia^{1

2}, Qiang Zhong^{1

2}, Zhongli Huang^{1

2}, Xianding Wang^{1

2}, Yu Fan^{1

2}, Tao Lin^{1

2}, Turun Song^{1

2}

Affiliations

¹ Urology Department, West China Hospital, Sichuan University, Chengdu, China.
² Organ Transplantation Center, West China Hospital, Sichuan University, Chengdu, China.
³ Urology Department, The Third People's Hospital of Chengdu, Chengdu, China.

^# Contributed equally.

Abstract

Background: Kidney ischemia-reperfusion (I/R) injury is an independent risk factor for delayed graft function after kidney transplantation with long-term graft survival deterioration. Previously, we found that the upregulated expression of miR-17-5p exerts a protective effect in kidney I/R injury, but the mechanism has not been clearly studied.

Methods: A kidney I/R injury model was induced in adult C57BL/6 male mice (20-22 g) by clamping both kidney pedicles for 30 min. The miR-17-5p agomir complex was injected into mice 24 h before surgery via the tail vein at a total injection volume of 10 µL/g body weight. The mice were euthanized on post-I/R injury day 2, and kidney function, apoptosis, autophagy, and related molecules were then detected. Human kidney-2 (HK-2) cells, which underwent hypoxia/reoxygenation, were treated with the miR-17-5p agomir, miR-17-5p antagomir, and small interfering ribonucleic acids (siRNAs). Cell viability, apoptosis, autophagy, and molecules were also examined.

Results: Autophagy, miR-17-5p expression, and kidney function damage were significantly more increased in the I/R group than in the sham group. In the cultured HK-2 cells underwent hypoxia/reoxygenation, the miR-17-5p agomir directly inhibited the expression of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and Bcl-2 like protein 11 (BIM), and attenuated apoptosis and autophagy. Further, miR-17-5p inhibited autophagy by activating the protein kinase B (Akt)/Beclin1 pathway, which was suppressed by siRNAs. Additionally, the administration of miR-17-5p agomir greatly improved kidney function in the I/R mice group by inhibiting autophagy and apoptosis.

Conclusions: These findings suggest a new possible therapeutic strategy for the prevention and treatment of kidney I/R injury. The upregulation of miR-17-5p expression appears to inhibit apoptosis and autophagy by suppressing PTEN and BIM expression, which in turn upregulates downstream Akt/Beclin1 expression.

Keywords: Autophagy; Bcl-2 like protein 11 (BIM); kidney ischemia-reperfusion injury (I/R injury); microRNA; phosphatase and tensin homolog deleted on chromosome 10 (PTEN).